Psychosocial and lifestyle impacts of spontaneous coronary artery dissection: A quantitative study.

IntroductionRecent studies suggest that acute myocardial infarction due to spontaneous coronary artery dissection (SCAD) carries significant psychosocial burden. This survey-based quantitative study builds on our earlier qualitative investigation of the psychosocial impacts of SCAD in Australian SCAD survivors. The study aimed to document the prevalence and predictors of a broad range of psychosocial and lifestyle impacts of SCAD.MethodAustralian SCAD survivors currently enrolled in the Victor Chang Cardiac Research Institute genetics study were invited to participate in an online survey to assess the psychosocial impacts of SCAD. Participants completed a questionnaire, developed using findings from our earlier qualitative research, which assessed 48 psychosocial and five lifestyle impacts of SCAD. Participants also provided demographic and medical data and completed validated measures of anxiety and depression.ResultsOf 433 SCAD survivors invited to participate, 310 (72%) completed the questionnaire. The most common psychosocial impacts were 'shock about having a heart attack' (experienced by 87% respondents), 'worry about having another SCAD' (81%), 'concern about triggering another SCAD' (77%), 'uncertainty about exercise and physical activity' (73%) and 'confusion about safe levels of activity and exertion' (73.0%) and 'being overly aware of bodily sensations' (73%). In terms of lifestyle impacts, the SCAD had impacted on work capacity for almost two thirds of participants, while one in ten had sought financial assistance. The key predictors of psychosocial impacts were being under 50, current financial strain, and trade-level education. The key predictors of lifestyle impacts were being over 50, SCAD recurrence, trade-level education, and current financial strain. All psychosocial impacts and some lifestyle impacts were associated with increased risk of anxiety and/or depression.Conclusion and implicationsThis quantitative study extends our previous qualitative investigation by documenting the prevalence of each of 48 psychosocial and five lifestyle impacts identified in our earlier focus group research, and by providing risk factors for greater SCAD impacts. The findings suggest the need for supports to address initial experiences of shock, as well as fears and uncertainties regarding the future, including SCAD recurrence and exercise resumption. Support could be targeted to those with identified risk factors. Strategies to enable SCAD survivors to remain in or return to the paid workforce are also indicated

Genetic Variation in the Proximal Promoter of ABC and SLC Superfamilies: Liver and Kidney Specific Expression and Promoter Activity Predict Variation

Membrane transporters play crucial roles in the cellular uptake and efflux of an array of small molecules including nutrients, environmental toxins, and many clinically used drugs. We hypothesized that common genetic variation in the proximal promoter regions of transporter genes contribute to observed variation in drug response. A total of 579 polymorphisms were identified in the proximal promoters (−250 to +50 bp) and flanking 5′ sequence of 107 transporters in the ATP Binding Cassette (ABC) and Solute Carrier (SLC) superfamilies in 272 DNA samples from ethnically diverse populations. Many transporter promoters contained multiple common polymorphisms. Using a sliding window analysis, we observed that, on average, nucleotide diversity (π) was lowest at approximately 300 bp upstream of the transcription start site, suggesting that this region may harbor important functional elements. The proximal promoters of transporters that were highly expressed in the liver had greater nucleotide diversity than those that were highly expressed in the kidney consistent with greater negative selective pressure on the promoters of kidney transporters. Twenty-one promoters were evaluated for activity using reporter assays. Greater nucleotide diversity was observed in promoters with strong activity compared to promoters with weak activity, suggesting that weak promoters are under more negative selective pressure than promoters with high activity. Collectively, these results suggest that the proximal promoter region of membrane transporters is rich in variation and that variants in these regions may play a role in interindividual variation in drug disposition and response

Common variants in P2RY11 are associated with narcolepsy.

l e t t e r s Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genomewide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3′ untranslated region of P2RY11, the purinergic receptor subtype P2Y 11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10 −10 , odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The diseaseassociated allele is correlated with reduced expression of P2RY11 in CD8 + T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases

Common variants in P2RY11 are associated with narcolepsy.

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y₁₁ gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10⁻¹⁰, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.journal articleresearch support, n.i.h., extramuralresearch support, non-u.s. gov'tresearch support, u.s. gov't, p.h.s.2011 Jan2010 12 19importedErratum in : Nat Genet. 2011 Oct;43(10):1040

Deletion distal to the PAX6 coding region reveals a novel basis for familial cosegregation of aniridia and diabetes mellitus

Aims: Analyze cosegregation of aniridia and diabetes to identify genetic criteria for detection and early treatment of diabetes-susceptible aniridia patients. Methods: We assessed a two-generation family: three individuals with aniridia, two previously diagnosed as type 2 diabetes. One individual with aniridia, with unknown diabetes status, was evaluated by oral glucose tolerance test. Genetic analysis of aniridia-associated genes was performed on all available family members. Candidate genes were functionally tested by gene silencing in MIN6 pancreatic β-cells. Results: A 25 year old male with aniridia had a diabetic oral glucose tolerance test despite a normal fasting blood glucose. A 484-630 kb deletion ∼120 kb distal to PAIRED BOX 6 (PAX6) showed dominant cosegregation with aniridia and diabetes in all affected family members. The deleted region contains regulatory elements for PAX6 expression and four additional coding regions. Knockdown of two of the deleted genes (Dnajc24 or Immp1l) with Pax6 impaired glucose-stimulated insulin secretion. Conclusions: We demonstrate dominant cosegregation of diabetes and aniridia with a deletion distal to PAX6, which is clinically distinct from the mild glucose intolerance previously reported with PAX6 coding mutations. Asymptomatic aniridia individuals appear at risk of diabetes (and its complications) and could benefit from earlier diagnosis and treatment

Pharmacological Enhancement of Regeneration-Dependent Regulatory T Cell Recruitment in Zebrafish

Regenerative capacity varies greatly between species. Mammals are limited in their ability to regenerate damaged cells, tissues and organs compared to organisms with robust regenerative responses, such as zebrafish. The regeneration of zebrafish tissues including the heart, spinal cord and retina requires foxp3a+ zebrafish regulatory T cells (zTregs). However, it remains unclear whether the muted regenerative responses in mammals are due to impaired recruitment and/or function of homologous mammalian regulatory T cell (Treg) populations. Here, we explore the possibility of enhancing zTreg recruitment with pharmacological interventions using the well-characterized zebrafish tail amputation model to establish a high-throughput screening platform. Injury-infiltrating zTregs were transgenically labelled to enable rapid quantification in live animals. We screened the NIH Clinical Collection (727 small molecules) for modulators of zTreg recruitment to the regenerating tissue at three days post-injury. We discovered that the dopamine agonist pramipexole, a drug currently approved for treating Parkinson’s Disease, specifically enhanced zTreg recruitment after injury. The dopamine antagonist SCH-23390 blocked pramipexole activity, suggesting that peripheral dopaminergic signaling may regulate zTreg recruitment. Similar pharmacological approaches for enhancing mammalian Treg recruitment may be an important step in developing novel strategies for tissue regeneration in humans

Common Variation in Fatty Acid Genes and Resuscitation From Sudden Cardiac Arrest

BACKGROUND: Fatty acids provide energy and structural substrates for the heart and brain and may influence resuscitation from sudden cardiac arrest (SCA). We investigated whether genetic variation in fatty acid metabolism pathways was associated with SCA survival. METHODS AND RESULTS: Subjects (mean age 67, 80% male, Caucasian) were out-of-hospital SCA patients found in ventricular fibrillation in King County, WA. We compared subjects who survived to hospital admission (n=664) with those who did not (n=689), and subjects who survived to hospital discharge (n=334) with those who did not (n=1019). Associations between survival and genetic variants were assessed using logistic regression adjusting for age, gender, location, time to arrival of paramedics, whether the event was witnessed, and receipt of bystander CPR. Within-gene permutation tests were used to correct for multiple comparisons. Variants in five genes were significantly associated with SCA survival. After correction for multiple comparisons, SNPs in ACSL1 and ACSL3 were significantly associated with survival to hospital admission. SNPs in ACSL3, AGPAT3, MLYCD, and SLC27A6 were significantly associated with survival to hospital discharge. CONCLUSIONS: Our findings indicate that variants in genes important in fatty acid metabolism are associated with SCA survival in this population

Common Variation in Fatty Acid Genes and Resuscitation From Sudden Cardiac Arrest

BackgroundFatty acids provide energy and structural substrates for the heart and brain and may influence resuscitation from sudden cardiac arrest (SCA). We investigated whether genetic variation in fatty acid metabolism pathways was associated with SCA survival.Methods and resultsSubjects (mean age, 67 years; 80% male, white) were out-of-hospital SCA patients found in ventricular fibrillation in King County, WA. We compared subjects who survived to hospital admission (n=664) with those who did not (n=689), and subjects who survived to hospital discharge (n=334) with those who did not (n=1019). Associations between survival and genetic variants were assessed using logistic regression adjusting for age, sex, location, time to arrival of paramedics, whether the event was witnessed, and receipt of bystander cardiopulmonary resuscitation. Within-gene permutation tests were used to correct for multiple comparisons. Variants in 5 genes were significantly associated with SCA survival. After correction for multiple comparisons, single-nucleotide polymorphisms in ACSL1 and ACSL3 were significantly associated with survival to hospital admission. Single-nucleotide polymorphisms in ACSL3, AGPAT3, MLYCD, and SLC27A6 were significantly associated with survival to hospital discharge.ConclusionsOur findings indicate that variants in genes important in fatty acid metabolism are associated with SCA survival in this population

In the Wrong Place with the Wrong SNP

BackgroundSudden cardiac arrest has been linked independently both to stressful neighborhood conditions and to polymorphisms in the ADRB2 gene. The ADRB2 gene mediates sympathetic activation in response to stress. Therefore, if neighborhood conditions cause cardiac arrest through the stress pathway, the ADRB2 variant may modify the association between neighborhood conditions, such as socioeconomic deprivation and incidence of cardiac arrest.MethodsThe Cardiac Arrest Blood Study Repository is a population-based repository of specimens and other data from adult cardiac arrest patients residing in King County, Washington. Cases (n = 1,539) were 25- to 100-year-old individuals of European descent who experienced out-of-hospital cardiac arrest from 1988 to 2004. Interactions between neighborhood conditions and the ADRB2 genotype on cardiac arrest risk were assessed in a case-only study design. Gene-environment independence was assessed in blood samples obtained from King County residents initially contacted by random-digit dialing.ResultsFewer than 4% of study subjects resided in socioeconomically deprived neighborhoods. Nonetheless, the case-only analysis indicated the presence of supramultiplicative interaction of socioeconomic deprivation and the homozygous Gln27Glu variant (case-only odds ratio: 1.8 [95% confidence interval: 1.0, 2.9]). Interactions between population density and the homozygous Gln27Glu variant were weaker (case-only odds ratio: 1.2 [95% confidence interval: 0.97, 1.5]).ConclusionsFindings support a supramultiplicative interaction between the Gln27Glu ADRB2 variant and socioeconomic deprivation among individuals of European descent. This result is consistent with the hypothesis that the elevation in cardiac arrest risk associated with socioeconomic deprivation operates through the stress pathway